Extensive Proliferation of Human Cancer Cells With Ever-Shorter Telomeres

Cell Rep. 2017 Jun 20;19(12):2544-2556. doi: 10.1016/j.celrep.2017.05.087.

Abstract

Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative. Here, we show that a subset of high-risk neuroblastomas (with ∼50% 5-year mortality) lacked significant TLM activity. Cancer cells derived from these highly aggressive tumors initially had long telomeres and proliferated for >200 population doublings with ever-shorter telomeres. This indicates that prevention of telomere shortening is not always required for oncogenesis, which has implications for inhibiting TLMs for cancer therapy.

Keywords: alternative lengthening of telomeres; ever-shorter telomeres; neuroblastoma; telomerase; telomeres.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation*
  • Enzyme Activation
  • Gene Amplification
  • Humans
  • N-Myc Proto-Oncogene Protein / genetics
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology
  • Telomerase / metabolism
  • Telomere Shortening*

Substances

  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Telomerase